Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: implications for erythrocyte functions

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Abstract

Purpose of review

The article summarizes new insights into the molecular mechanisms for the maintenance and regulation of the asymmetric distribution of phospholipids in human erythrocyte membranes. We focus on phosphatidylserine, which is primarily found in the inner leaflet of the membrane lipid bilayer under low Ca2+ conditions (<1 μmol/l) and is exposed to the outer leaflet under elevated Ca2+ concentrations (>1 μmol/l), when cells become senescent. Clarification of the molecular basis of phosphatidylserine flipping and scrambling is important for addressing long-standing questions regarding phosphatidylserine functions.

Recent findings

ATP11C, a P-IV ATPase, has been identified as a major flippase in analyses of patient erythrocytes with a 90% reduction in flippase activity. Phospholipid scramblase 1 (PLSCR1) has been defined as a Ca2+-activated scramblase that is completely suppressed by membrane cholesterol under low Ca2+ concentrations.

Summary

For survival, phosphatidylserine surface exposure is prevented by cholesterol-mediated suppression of PLSCR1 under low Ca2+ concentrations, irrespective of flipping by ATP11C. In senescent erythrocytes, PLSCR1 is activated by elevated Ca2+, resulting in phosphatidylserine exposure, allowing macrophage phagocytosis. These recent molecular findings establish the importance of the maintenance and regulation of phosphatidylserine distribution for both the survival and death of human erythrocytes.

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